US20220401565A1 - Medical uses of thiol-functionalized polyglycerol derivatives - Google Patents

Medical uses of thiol-functionalized polyglycerol derivatives Download PDF

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US20220401565A1
US20220401565A1 US17/764,179 US202017764179A US2022401565A1 US 20220401565 A1 US20220401565 A1 US 20220401565A1 US 202017764179 A US202017764179 A US 202017764179A US 2022401565 A1 US2022401565 A1 US 2022401565A1
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polyglycerol
backbone
integer
derivative
thiol
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Rainer Haag
Marcus Mall
Daniel Lauster
Yinan Zhong
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Charite Universitaetsmedizin Berlin
Freie Universitaet Berlin
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Freie Universitaet Berlin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • C08G65/3342—Polymers modified by chemical after-treatment with organic compounds containing sulfur having sulfur bound to carbon and hydrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/48—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched
    • C08G2650/32—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched dendritic or similar
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/52—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type obtained by dehydration of polyhydric alcohols
    • C08G2650/54—Polyglycerols

Definitions

  • the disclosure relates to methods of treatment of a human or animal patient which are carried out by administering a polyglycerol derivative, to a thiol-functionalized polyglycerol derivative and to a method for manufacturing such a thiol-functionalized polyglycerol derivative.
  • mucus The human mucosal surfaces (mucosa) are covered with a thin hydrobiopolymer called mucus that has important homeostatic functions and protects those surfaces from dehydration or infection.
  • Mucus consists of highly glycosylated mucin monomers (up to 80% sugar content), which allows hydrogels to form in the presence of water. These mucin monomers in turn can form disulfide bridges by oxidation and thus multimerize.
  • mucus solid matter concentrations of approximately 10 mg/ml (percentage of dry mass with respect to moist mass) are found in humans. This concentration can increase massively (up to 80 to 100 mg/ml) in some diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) or bronchial asthma.
  • CF cystic fibrosis
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma bronchial asthma.
  • NAC N-acetylcysteine
  • US 2005/0260140 A1 describes mucolytic and anti-elastase compounds. These compounds contain a dithiol active-site.
  • compositions and methods for decreasing the viscosity of excessively viscous mucus contain an enzyme like an oxidoreductase containing a thioredoxin monocysteinic active site in a reduced state in its catalytic center. It might furthermore contain a reducing system.
  • DE 26 02 196 A1 describes pharmaceutical agents for human and veterinary medicine containing DL-2-amino-4-(carboxymethylthio)butyric acid having mucolytic activity and a regenerative effect on lung and bronchial tissue.
  • US 2015/0307530 A1 describes a method of liquefying mucus from mucosal surfaces by administering compounds containing a phosphine group.
  • WO 98/38995 A1 describes the use of 2-methyl-thiazolidine-2,4-dicarboxylic acid and/or its physiologically tolerable salts as mucolytic agents.
  • U.S. Pat. No. 4,210,666 A describes 2-Thiophenecarboxamido-alkylmercaptans with a straight or branched divalent alkylene radical of 2 to 4 carbon atoms and methods of using the compounds as mucolytic agents in combating lung mucus and compositions for use as mucolytic agents.
  • U.S. Pat. No. 3,567,835 A discloses salts of mercaptoalkane sulphonic acids of the general formula HS—X—SO 3 H, wherein X is a C2-6 straight or branched chain alkylene radical.
  • the compositions are particularly useful for treatment of diseases of the respiratory tract.
  • U.S. Pat. No. 9,346,753 B2 discloses dithiol mucolytic agents. These agents increase the liquefaction of mucus in a patient with excessive mucus or mucus with increased viscoelastic, cohesive, or adhesive properties. Also disclosed are a variety of methods of treatment using these mucolytic agents.
  • WO 2016/123335 A1 and WO 2016/176423 A1 describe mucolytic agents with an aryl-based core as well as methods of treatment which take advantage of the mucolytic properties of these agents.
  • cystic fibrosis airway mucus gels have a molecular architecture characterized by a core of mucin covered by a web of DNA and a rheological profile characterized by high elasticity that can be normalized by chemical reduction.
  • Methyl 6-thio-6-deoxy- ⁇ -d-galactopyranoside was synthesized and found to have stronger reducing activity than NAC and more potent and fast-acting mucolytic activity in cystic fibrosis sputum. This publication further suggests that pathologic mucus gel formation in the lung can be generally targeted by thiol-modified carbohydrates.
  • EP 0 045 285 A1 describes macromolecular compounds of mucolytic activity, constituted by carbohydrates as their basic structure, to which proteolytic enzymes and sulfhydryl groups are bonded by suitable aliphatic chains.
  • WO 2014/153009 A2 describes a thiosaccharide mucolytic agent useful for decreasing mucus elasticity or decreasing mucus viscosity in a subject in need thereof.
  • this object is achieved by the further medical use, in particular the therapeutic use, of a polyglycerol derivative as mucolytic.
  • this polyglycerol derivative comprises a linear or dendritic polyglycerol backbone and carries at least one thiol group covalently bound to the polyglycerol backbone.
  • the thiol group can be bound directly or indirectly to the polyglycerol backbone.
  • Thiol-functionalized hydrophilic polyglycerols can effectively penetrate the mucus gel and break disulfide bridges. If the polyglycerols additionally carry sulfate groups, they also have anti-inflammatory properties that are helpful in curing inflammations that might be causative for an excessive mucus production or that might occur in the course of excessive mucus production.
  • the mucolytic is a mucolytic for mucus of the respiratory tract, in particular for pulmonary mucus. In another embodiment, the mucolytic is a mucolytic for gastrointestinal mucus, in particular for intestinal mucus.
  • the solution relates to the further medical use of a polyglycerol derivative for use in treating chronic sinusitis, asthma, chronic bronchitis, cystic fibrosis, chronic obstructive pulmonary disease, emphysema, or bronchiectasis.
  • diseases are diseases caused by or connected to an excess mucus production in the lung and/or a higher mucus viscosity than in healthy people.
  • the polyglycerol derivative has a linear or dendritic polyglycerol backbone and carries at least one thiol group covalently bound to the polyglycerol backbone. Also for this aspect, the thiol group can be bound directly or indirectly to the polyglycerol backbone.
  • the solution relates to the further medical use of a polyglycerol derivative for use in treating chronic inflammatory bowel diseases, constipation gastrointestinal malabsorption syndrome, irritable bowel syndrome, steatorrhea or diarrhea.
  • diseases are diseases caused by or connected to an excess mucus production in the gastrointestinal tract and/or a higher mucus viscosity than in healthy people.
  • the polyglycerol derivative has a linear or dendritic polyglycerol backbone and carries at least one thiol group covalently bound to the polyglycerol backbone. Also for this aspect, the thiol group can be bound directly or indirectly to the polyglycerol backbone.
  • the solution relates to the further medical use of the same polyglycerol derivative as outlined above for use in reducing mucus viscosity.
  • the solution relates to the further medical use of the same polyglycerol derivative as outlined above for use in treating mucinous neoplasias, e.g., pseudomyxoma peritonei or mucinous adenocarcinoma.
  • mucinous neoplasias e.g., pseudomyxoma peritonei or mucinous adenocarcinoma.
  • the polyglycerol backbone carries a plurality of sulfate groups, wherein a degree of sulfation of the polyglycerol backbone is between 10 and 100%. Particularly appropriate degrees of sulfation are between 50% and 100%, between 70% and 100%, between 85% and 100%, and in particular between 90% and 100%.
  • sulfating the polyglycerol derivatives anti-inflammatory properties are transferred onto the polyglycerol derivatives. Thereby, this effect is particularly pronounced if the degree of sulfation is at least 70%.
  • the degree of sulfation indicates the relative amount of hydroxyl groups of the polyglycerol derivative that have been exchanged by sulfate groups.
  • the polyglycerol backbone carries 1 to 100 thiol groups per polyglycerol derivative molecule, in particular 2 to 90, in particular 3 to 80, in particular 4 to 70, in particular 5 to 60, in particular 6 to 50, in particular 7 to 40, in particular 8 to 30, in particular 9 to 20, in particular 10 to 19, in particular 11 to 18, in particular 12 to 17, in particular 13 to 16, in particular 14 to 15 thiol groups per polyglycerol derivative molecule.
  • the thiol groups are typically statistically distributed over the whole polyglycerol derivative molecule.
  • the mucolytic effect can already be achieved with statistically one thiol group per polyglycerol derivative molecule.
  • the thiol-functionalization of the polyglycerol derivative is realized in form of a dithiol (i.e., two thiol groups per substituent covalently bound to the polyglycerol backbone).
  • the polyglycerol backbone is biodegradable. This can be achieved, e.g., by manufacturing the polyglycerol backbone by a reaction randomly combining glycerol units and ⁇ -caprolactone units. Such a manufacturing method is disclosed, e.g., in WO 2019/096782 A1. Other biodegradable architectures of the polyglycerol backbone of the polyglycerol derivatives can also be realized.
  • the at least one thiol group is directly bound to the polyglycerol backbone without any intermediate linker.
  • the at least one thiol group is indirectly bound to the polyglycerol backbone via a linker. In this regard, different linker generally possible.
  • polyglycerol derivative corresponds to the following general formula (T)
  • the cationic counter ion is an ion of an alkali metal, in particular a sodium ion (Na + ) or a potassium ion (K + ).
  • n is an integer between 10 and 4000, in particular between 15 and 3500, in particular between 20 and 3000, in particular between 50 and 2500, in particular between 100 and 2000, in particular between 200 and 1500, in particular between 500 and 1000.
  • p is an integer between 10 and 4000, in particular between 15 and 3500, in particular between 20 and 3000, in particular between 50 and 2500, in particular between 100 and 2000, in particular between 200 and 1500, in particular between 500 and 1000.
  • R 5 comprises 2 to 19, in particular 3 to 18, in particular 4 to 17, in particular 5 to 16, in particular 6 to 15, in particular 7 to 14, in particular 8 to 13, in particular 9 to 12, in particular 10 or 11 amino acid residues, wherein at least one amino acid residue is a cysteine residue.
  • the amino acid residues of residue R 5 are chosen from the group of standard amino acid residues.
  • the solution does not only relate to novel medical uses of polyglycerol derivatives, but to these polyglycerol derivatives themselves.
  • the solution relates to a polyglycerol derivative corresponding to the following general formula (I):
  • the cationic counter ion is an ion of an alkali metal, in particular a sodium ion (Na + ) or a potassium ion (K + ).
  • the polyglycerol derivative comprises a linear polyglycerol backbone.
  • the whole polyglycerol backbone of the polyglycerol derivative is linear.
  • the polyglycerol derivative can be denoted as linear polyglycerol derivative (lPG) in these embodiments.
  • lPG linear polyglycerol derivative
  • a 1,2-linkage and/or a 1,3-linkage can be established between the individual glycerol units of the polyglycerol derivative.
  • the polyglycerol derivative comprises a dendritic polyglycerol backbone.
  • the whole polyglycerol backbone of the polyglycerol derivative is dendritic.
  • the dendritic backbone of the polyglycerol derivative can also be denoted as hyperbranched backbone.
  • the polyglycerol derivative can be denoted as dendritic polyglycerol (dPG) or hyperbranched polyglycerol (hPG).
  • dPG dendritic polyglycerol
  • hPG hyperbranched polyglycerol
  • Hyperbranched polyglycerol sulfates express little or no anticoagulant effect.
  • the residue X is:
  • the residue X is:
  • the residue X is:
  • o is 1.
  • the residue X is:
  • the residue X is:
  • the residue X is:
  • the residue X is:
  • the residue X is:
  • the residue X is:
  • an aqueous solution of 2-iminothiolane hydrochloride is added to an aqueous solution of an amine-functionalized polyglycerol derivative corresponding to the following general formula (II):
  • This reaction can take place, e.g., at a temperature between 0° C. and 50° C., such as room temperature.
  • An appropriate reaction duration is 10 minutes to 24 hours, in particular 20 minutes to 20 hours, in particular 30 minutes to 15 hours, in particular 40 minutes to 12 hours, in particular 50 minutes to 10 hours, in particular 1 hour to 8 hours, in particular 2 hours to 6 hours, in particular 3 hours to 4 hours.
  • a particularly appropriate reaction duration lies between 30 minutes and 90 minutes, i.e., around 1 hour.
  • the solution relates to a second method for manufacturing a polyglycerol derivative according to the preceding explanations. This method is carried out by performing the steps explained in the following.
  • a solution of mercaptoacetic acid and an activation reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) in water or a polar aprotic solvent is added to a solution of an amine-functionalized polyglycerol derivative corresponding to the following general formula (II) in water or a polar aprotic solvent:
  • An appropriate polar aprotic solvent is, e.g., dimethyl sulfoxide (DMSO).
  • An appropriate total reaction duration is 10 minutes to 48 hours, in particular 20 minutes to 36 hours, in particular 30 minutes to 24 hours, in particular 40 minutes to 20 hours, in particular 50 minutes to 12 hours, in particular 1 hour to 10 hours, in particular 2 hours to 8 hours, in particular 3 hours to 6 hours, in particular 4 hours to 5 hours.
  • a particularly appropriate duration for the first reaction step is 10 minutes to five hours, in particular 20 minutes to 4 hours, in particular 30 minutes to 2 hours, in particular 40 minutes to 1.5 hours, in particular 50 minutes to 1 hour.
  • a particularly appropriate duration for the second reaction step is 1 hour to 48 hours, in particular 5 hours to 36 hours, in particular 10 hours to 30 hours, in particular 15 hours to 26 hours, in particular 20 hours to 24 hours.
  • the reaction might be carried out such that it is performed during 4 hours (e.g., at 50° C.) in a first step and during 24 hours (e.g., at room temperature) in a second step.
  • the amine-functionalized polyglycerol derivative and the thiol-functionalized polyglycerol derivative are linear polyglycerol derivatives.
  • the amine-functionalized polyglycerol derivative and the thiol-functionalized polyglycerol derivative are dendritic polyglycerol derivatives.
  • the solution relates to a method of treatment of a human or animal patient in need thereof to achieve a reduction of the viscosity of mucus of the patient.
  • This method is carried out by administering a polyglycerol derivative having a linear or dendritic polyglycerol backbone and carrying at least one thiol group covalently bound to the polyglycerol backbone to the patient.
  • this method aims in reducing the amount of mucus in or on an organ of the patient by enabling an easier decomposition and discharge of the mucus.
  • the solution relates to a method of treatment of a human or animal patient suffering from chronic sinusitis, asthma, chronic bronchitis, cystic fibrosis, chronic obstructive pulmonary disease, emphysema, or bronchiectasis and being in need of such treatment by administering a polyglycerol derivative having a linear or dendritic polyglycerol backbone and carrying at least one thiol group covalently bound to the polyglycerol backbone to the patient.
  • the solution relates to a method of treatment of a human or animal patient suffering from chronic inflammatory bowel diseases, constipation, gastrointestinal malabsorption syndrome, irritable bowel syndrome, steatorrhea or diarrhea and being in need of such treatment by administering a polyglycerol derivative having a linear or dendritic polyglycerol backbone and carrying at least one thiol group covalently bound to the polyglycerol backbone to the patient.
  • FIG. 1 shows synthetic routes for manufacturing different thiol-containing polymers.
  • FIG. 2 A shows a 1 H NMR spectrum (600 MHz, D 2 O) of dPGS-NH 2 .
  • FIG. 2 B shows a 1 H NMR spectrum (600 MHz, D 2 O) of dPGS-SH.
  • FIG. 3 shows a calibration curve of 3-mercaptopropionic acid solution.
  • FIG. 4 A shows a 1 H NMR spectrum (600 MHz, D 2 O) of dPG-NH 2 .
  • FIG. 4 B shows a 1 H NMR spectrum (600 MHz, D 2 O) of dPG-SH.
  • FIG. 5 shows a 1 H NMR spectrum (600 MHz, D 2 O) of dPGS-LA(SH).
  • FIG. 6 shows a synthetic route for manufacturing dPGS-mercaptoacetic acid.
  • FIG. 7 shows the influence of a treatment of cystic fibrosis mucus with different mucolytics on the elastic modulus of the mucus.
  • FIG. 8 shows the influence of a treatment of cystic fibrosis mucus with different mucolytics on the viscosity of the mucus.
  • FIG. 9 shows a reaction scheme of the synthesis of lPG-dithiol via mesylation.
  • FIG. 10 A shows half-wave potential of DTT and thiol-containing polyglycerols from cyclic voltammetry measurements.
  • FIG. 10 B shows the thiol concentration of two batches of dPGS-SH after synthesis, and after a 10-month storage as lyophilisate at 4° C.
  • FIG. 10 C shows a Western blot of mucus samples from bronchoalveolar lavage (BAL) of ⁇ ENaC-Tg mice subjected to increasing concentrations of dithiothreitol (DTT), N-acetylcysteine (NAC) and dPGS-SH (0.2-20 mM).
  • DTT dithiothreitol
  • NAC N-acetylcysteine
  • dPGS-SH 0.2-20 mM
  • Dendritic polyglycerol sulfate-thiol (dPGS-SH) was obtained via the reaction between dPGS-amine (dPGS-NH 2 , 38.5 kDa, sulfate: 81.7 mol. %, amine: 10.7 mol. %) and 2-iminothiolane hydrochloride (Sigma, 98%) ( FIG. 1 , reaction scheme A).
  • dPGS-NH 2 38.5 kDa, sulfate: 81.7 mol. %, amine: 10.7 mol. %)
  • 2-iminothiolane hydrochloride (Sigma, 98%)
  • the reaction continued at room temperature (r.t.) for 1 h with a pH of 7.0 by adding KOH solution. Afterwards, the target polymer dPGS-SH was purified via ultrafiltration, and obtained as light yellow powder after lyophilization. The yield was 87%.
  • Dendritic polyglycerol-thiol (dPG-SH) was obtained via the reaction between dPG-amine (dPG-NH 2 , 10.0 kDa, amine: 10.0 mol %) and 2-iminothiolane hydrochloride (Sigma, 98%) ( FIG. 1 , reaction scheme B).
  • dPG-NH 2 0.5 g, 8 mL
  • 2-iminothiolane hydrochloride 42 mg in 2 mL of the same solvent system, 1.2 eq.
  • the reaction continued at r.t. for 1 h with a pH of 7.0 by adding KOH solution.
  • the target polymer dPG-SH was purified via ultrafiltration, and obtained as light yellow oil after lyophilization. The yield was 85%.
  • the dithiol-containing dPGS was obtained in the following three steps ( FIG. 1 , reaction scheme IC): i) the formation of lipoic acid anhydride (LAA) at the presence of dicyclohexylcarbodiimid (DCC), ii) the reaction between LAA and dPGS-NH 2 via the catalysis of N,N-4-dimethylaminopyridine (DMAP), and iii) the breakage of the disulfide bond in LA at the presence of dithiothreitol (DTT).
  • LAA lipoic acid anhydride
  • DCC dicyclohexylcarbodiimid
  • DMAP N,N-4-dimethylaminopyridine
  • DTT dithiothreitol
  • the obtained LAA was then dissolved in 5 mL DMSO, and added into the solution of dPGS-NH 2 (0.6216 g) in 10 mL DMSO at the presence of DMAP (120 mg). The reaction proceeded under stirring for 48 h at room temperature in the dark. Finally, DTT (246 mg) was added into the resulting solution and reacted for 24 h under stirring at r.t.
  • the target polymer dPGS-LA(SH) was purified via dialysis in degassed deionized water under an argon atmosphere for 48 h, and freeze-dried. The yield was 74%.
  • 1 H NMR 600 MHz, D 2 O
  • the target polymer dPGS-LA(SH) was purified via dialysis in degassed deionized water under an argon atmosphere for 48 h, and freeze-dried.
  • the stability of the manufactured dPGS-SH was tested by determining its thiol content immediately after manufacturing the compound and once again after a plurality of months (6 months or 10 months, respectively). According to the results depicted in Table 1, no significant difference between the individual measurements of the same sample could be observed. Thus, the thiol group remains stable in dPGS-SH even after a prolonged storage.
  • dPGS-SH dPG(S)-mercapto carboxylic acid
  • dPG(S)-DTT dPG(S)- ⁇ -mercaptoethanol
  • dPG(S)-cysteamine dPG(S)-cysteine
  • dPGS-mercaptoacetic acid (a specific example of dPG(S)-mercapto carboxylic acid)
  • the conjugation is conducted by adding a solution of mercaptoacetic acid (35 mg, 4.5 eq.) and EDCl (94.7 mg, 5.9 eq.) in DMSO (15 mL) to a solution of dPGS-amine (1 g, 0.084 mmol) in DMSO (5 mL).
  • the mixture is then stirred at 50° C. for 4 h and at r.t. for 24 h.
  • the solvent will be evaporated under reduced pressure, and the raw product is dissolved in degassed Milli Q water, dialyzed against the same media for three days, and lyophilized to remove water.
  • the reaction scheme is depicted in FIG. 6 . It is apparent that the synthesis of dPG-mercaptoacetic acid can be achieved in the same manner as the synthesis of dPGS-mercaptoacetic acid. The reaction could likewise be performed in the same manner with a linear polyglycerol or a linear polyglycerol sulfate.
  • rheological properties of lung mucus which was collected from patients with cystic fibrosis, were determined before and after treatment with different reducing or control agents.
  • mucus from a healthy donor was used as control.
  • Rheological measurements can be generally used to determine both elastic and viscous material components.
  • dPGS thiol-functionalized dendritic polyglycerol sulfate
  • DTT Dithiothreitol
  • FIG. 8 shows a depiction of the viscosity over the frequency and confirms the results explained with respect to FIG. 7 .
  • treatment of CF mucus with dPGS-SH results in a mucus viscosity that corresponds to the mucus viscosity of healthy mucus.
  • NAC does not show any enhanced mucolytic activity than PBS.
  • DTT completely destroys the viscosity properties of mucus and thus impairs the physiologic functionality of mucus.
  • FIG. 9 The four-step reaction scheme of this synthesis is depicted in FIG. 9 . It will be briefly explained in the following. Notably, this synthesis is not limited to linear polyglycerol backbones but generally works with almost every hydroxyl functionalization, i.e. in particular also with dendritic polyglycerol backbones.
  • the resulting lPEEGE (b) was purified by a 1.5-days dialysis against acetone.
  • FIGS. 10 A to 10 D show the results of studies on the effects of dPGS-SH on biochemical and rheological properties of mucus from mice with CF-like lung disease and patients with CF.
  • redoxpotentials were determined using cyclic voltammetry and compared to that of DTT ( FIG. 10 A).
  • the compounds were measured at 5 mM thiol content in DMSO against a ferrocinium/ferrocene reference electrode.
  • the dPG(S)-SH systems demonstrated a higher redoxpotential than DTT.
  • the thiol concentration was determined with the Ellman's assay (using 5,5′-dithiobis-(2-nitrobenzoic acid) or DTNB as reagent) immediately after synthesis and 10 months later ( FIG. 10 B). Upon storage as lyophilisate at 4° C. the thiol-content of dPGS-SH did not change significantly for a period of 10 months. Regarding the compound stability, this aspect is an important finding.
  • the mucolytic activity was probed on mucus samples from CF patients ( FIG. 10 D).
  • the collected mucus was kept on ice or treated for 30 minutes at 37° C. with the indicated reducing agent or a buffer control. After the treatment, the samples were quenched with 50 mM iodoacetamide and put on ice until they underwent rheological measurements.
  • the storage modulus of human mucus could be decreased with all reducing agents.
  • the reducing efficacy of dPGS-SH was lower than that of DTT, but higher than the clinically approved drug NAC at equimolar concentrations.

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EP19200288.9A EP3797783A1 (fr) 2019-09-27 2019-09-27 Nouvelles utilisations médicales de dérivés de polyglycérol fonctionnalisés de thiol
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GB1119721A (en) 1965-05-07 1968-07-10 Ucb Sa Mucolytic mercapto-sulphonates
DE2602196A1 (de) 1976-01-21 1977-07-28 Jean Dr Ing Blum Pharmazeutische mittel mit 2-amino-4-carboxymethylthio-buttersaeure
US4210666A (en) 1978-08-10 1980-07-01 A. H. Robins Company, Inc. Mucolytic thiophenecarboxamido alkyl mercaptans
IT1209419B (it) * 1980-07-01 1989-07-16 Texcontor Ets Composti ad attivita' mucolitica non assimilabili, processo per laloro preparazione e composizioni terapeutiche che li comprendono come principio attivo.
DE19711052C2 (de) 1997-03-03 1999-09-23 Hans Rommelspacher Verwendung von 2-Methyl-thiazolidin-2,4-dicarbonsäure als Mukolytikum
US7345051B2 (en) 2000-01-31 2008-03-18 Genaera Corporation Mucin synthesis inhibitors
US7195766B2 (en) 2002-09-10 2007-03-27 National Jewish Medical And Research Center Product and process for liquefaction of mucus or sputum
WO2014036445A2 (fr) 2012-08-31 2014-03-06 Johnson Michael R Nouveaux agents mucolytiques
WO2014140428A1 (fr) 2013-03-14 2014-09-18 Ahlstrom Corporation Procédé de fabrication d'un milieu filtrant mince
CA3123075C (fr) * 2013-03-14 2023-09-19 The Regents Of The University Of California Agents mucolytiques thiosaccharidiques
BR112016003481A2 (pt) 2013-08-23 2020-03-03 Parion Sciences, Inc. Agentes mucolíticos de ditiol
BR112017016067A2 (pt) 2015-01-30 2018-04-03 Parion Sciences Inc agentes mucolíticos de monotiol
CN107708680A (zh) 2015-04-30 2018-02-16 帕里昂科学公司 新的二硫醇粘液溶解剂的前药
EP3483201A1 (fr) 2017-11-14 2019-05-15 Freie Universität Berlin Procédé de fabrication d'un dérivé de polyol de polyester hyperramifié

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